Abstract We recently reported that the proinflammatory cytokine hormone leptin accelerated the development and progression of systemic lupus erythematosus (SLE) in lupus-prone (NZB x NZW)F1 (NZB/W) mice. Interestingly, leptin inhibition in severely nephritic NZB/W mice associated with a significant increase in survival and amelioration of multiple disease manifestations, suggesting that this approach could represent a new modality of therapeutic intervention in the disease. Building on these findings, we aim to test the possibility of leptin-based intervention in human SLE for the reduction of circulating autoantibodies, delayed disease progression, and improved outcomes. Specifically, we developed fully human anti-leptin and anti- leptin receptor monoclonal antibodies (mAb) that will be tested in two different mouse model systems reconstituted with human cells through the following specific aims: 1) To evaluate the in vivo therapeutic efficacy of leptin inhibition in SLE using human mAb in humanized lupus mice; 2) To investigate the mechanisms induced in vivo by leptin blockade. Together, these studies will inform about the efficacy of leptin antagonism in human SLE, laying critical grounds for subsequent clinical trials in the disease.